Nephritis-Associated Streptococcal Antigens

The systematic search for the nephritogenic antigen in Group A streptococcus started more than 40 years ago with the evaluation of the M protein (1–4). The spotlight moved slowly away from M protein because the increasing number of nephritogenic M types (streptococci isolated from patients with nephritis) contrasted with the notion of a single nephritogen that would confer long-lasting immunity, which was suggested by the time-honored observation that second attacks of PSGN are extremely rare. In addition, its localization in the glomeruli of patients with PSGN remained inconclusive or difficult to repeat (5). Subsequent studies tested nephritogenicity on the basis of the finding that fluorescein-labeled convalescent sera, independently of the M type of the original infection, was capable of staining early biopsies with presumably free streptococcal antigen deposits (6). However, later studies showed that convalescent sera has anti-Ig rheumatoid factor activity that could be responsible for the positive staining of Ig-positive biopsies (7,8). Other studies focused on antigen(s) isolated from supernatants of pressure-disrupted streptococcal cultures (9), cationic streptococcal proteins (10), cell membrane antigens (11), and a nephritis strain–associated protein later identified as streptokinase (12,13). In the last decade, the streptococcal plasmin receptor (Plr), which is the subject of the paper by Yoshizawa et al. in this issue of the JASN (14), and the streptococcal cationic proteinase exotoxin B (SPEB) and its zymogen precursor (15–17) have been extensively investigated. The article by Yoshizawa et al. (14) provides important evidence to expand previous the investigations showing that this antigen has functional activity and amino acid sequence identical with the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of Bacillus subtilis (18). The purified Plr was obtained from nephritis-associated strains, therefore named NAPlr, but it is identical with Plr from other streptococcal strains; as reported previously by the authors (18), 92% of the acute PSGN patients had positive serum anti-NAPlr antibodies, and about 80% of the renal biopsies obtained in the first 30 d of PSGN showed deposits of NaPlr. The authors postulate that NaPlr in the mesangium may interact with plasmin(ogen), which may in turn cause glomerular damage by degrading glomerular basement membrane (GBM) through activation of metalloproteinase precursors; then, circulating immune complexes could move across the altered GBM and accumulate in the subepithelial space. The evidence in this article (14) is compellingly in favor of a nephritogenic role for NAPlr, and it may be asked whether this is the long-sought streptococcal antigen that causes PSGN. Several aspects need to be considered in relation to this question. Elevated serum antibody titers to other putative nephritogens have been found in patients with acute PSGN. For instance, anti-SPEB and antizymogen antibody levels discriminate between infections associated with nephritis and other streptococcal infections in the skin and throat, infections associated with rheumatic fever, and/or uncomplicated scarlet fever (16,17). Since all the patients with PSGN in the Yoshisawa et al. study (14) had increased antistreptolysin O (ASO) titers and ASO titers are frequently normal in streptococcal pyodermitis, it may be assumed that most, if not all, the PSGN patients in this study had preceding upper respiratory infections. Consistent with this assumption is their selection of patients with upper respiratory infections without nephritis as a suitable group for comparison. Therefore, the findings in the study by Yoshizawa et al. (14) may not be applicable to post-impetigo PSGN. In addition, anti-NAPlr reactivity in sera was tested by Western blot analysis and the reported titers determined in relation to the density of the positive control band and to the band in age-matched healthy controls; perhaps it might have been preferable to use ELISA methodology to better define antibody titers. Nevertheless, NAPlr antibody levels discriminate better than ASO titers and ASK between nephritis-associated and non-associated streptococcal infections. Moreover, the persistence of elevated titers over at least 10 yr after the acute attack indicate that antibody response is long lasting. The antibody titers to other potential nephritogens, such as SEPB, have been shown to be elevated 1 yr after the acute attack (17), but the studies of Yoshizawa et al. offer the longest follow-up of the antibody response to potential nephritogens. The glomerular deposits of NAPlr were found in all the biopsies obtained in the first 2 wk of the disease and predominate in the mesangium, where the plasminogen deposits are also located. In these early biopsies, only complement components were demonstrated with similar consistency. After 30 d, the biopsies were all NAPlr-negative, emphasizing the need for early biopsies in studies directed to demonstrate antigens in the kidney. The authors note that infiltrating leukocytes stain positive in a ring-like pattern, but an explanation for this finding is not offered. Other investigators have localized streptococcal antigens in the glomeruli, but less frequently. For instance, Vogt et al. (10) found cationic antigens (at that time of undefined nature) in 8 of 18 biopsies, and Cu et al. (17) demonstrated SPEB in 12 or 18 biopsies of acute PSGN. In summary, the article by Yoshizawa et al. (14) expands the careful investigations that this research group has completed on the association of streptococcal Plr and glomerulonephritis. Taken together with other available evidence, their work contributes to strengthen the following emerging conclusions regarding nephritogenic streptococcal fractions and PSGN. There are now well-characterized streptococcal antigens, among them NAPlr, that induce long-lasting antibody response and are localized in the glomeruli of patients with the disease. In the absence of an undisputed animal model for PSGN, this is the best we can do to presume pathogenetic relevance. Streptococcal antigens with a claim to nephritogenicity are not only present in streptococci of the M types traditionally associated with glomerulonephritis, not even exclusively in group A streptococci. This is the case for both NAPlr and for the cationic SPEB/zymogen, and it implies that the potential to cause nephritis is more widely distributed among streptococcal strains than traditionally accepted. Congruent with this interpretation is the sporadic cases and epidemics of PSGN caused by group C streptococci (19–20). Plasmin may be a common final pathway engaged by several antigens capable of causing PSGN. Plasmin-binding properties are characteristic of both NaPlr and SEPB, and the possibility that activated plasmin may be involved in activation of complement, chemotaxis, and degradation of GBM components has been raised by investigators championing both these antigenic fractions (15, 18).